A comprehensive study of the mechanisms by which peptide hormones, angiotensin and bradykinin stimulate the release of prstaglandins from perfused organs offers 1. a means of probing cellular regulation of prostaglandin metabolism, and 2. a possible means for optimizing delivery of cytotoxic drugs to malignant tissue. Peptide mediated release of prostaglandins is not observed with all isolated organ preparations suggesting a specific mechanism or site of action for the peptides. Not yet fully defined is the correlation between prostaglandin release and vascular activity of the peptide. We will synthesize analogs of these peptides, infuse them into several model, isolated organ preparations and determine the quantities and types of prostaglandins released. Prostaglandin release from any tissue reflects the net result of synthesis and degradation. To identify mechanisms by which peptides affect prostaglandin metabolism, we will isolate and characterize PG synthetase, phospholipase A2 and 15-OH PG dehydrogenase from both "responding" and "non-responding" tissues. One of our goals will be to identify those peptides (and other agents) whose primary physiological activity is mediated through the local release of prostaglandins. Since organ perfusion is one determinant of drug distribution, agents which stimulate the local release of prostaglandins, may enhance selective toxicity of cytotoxic drugs. Thus, controlled intra-tissue generation of prostaglandins may provide a new approach for improving the pharmacokinetics of chemotherapeutic agents.